Arylated amides of furan and thiophene carboxylic acids with effect inhibiting potassium channel

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylated amides of furan and thiophene carboxylic acids of the formulae (Ia) and (Ib) wherein W means oxygen or sulfur atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x means 0, 1, 2 or 3; R(14) means phenyl, and to their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition and using proposed compounds a medicinal agents. Compounds can be used as anti-arrhythmic biologically active substances and especially in treatment and prophylaxis of atrium arrhythmia.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 29 ex

 

The present invention relates to compounds of formula (Ia) and formula (Ib)

their acquisition and their application, particularly in medicines

where X means an oxygen atom or a sulfur atom;

R(1) means C(O)OR(9), SO2R(10), COR(11), C(O)NR(12)R(13) or C(S)NR(12)R(13);

moreover, R(9)R(10)R(11) R(12)

independently from each other mean WithxH2-R(14),

where x is 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15) or SO2CH3;

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5C3F7CH2F, CHF2, OR(15), SO2CH3, phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 atoms is of Pereda, CF3or phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(13) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(2) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(3) meansyH2y-R(16),

where y is 0, 1, 2, 3,or 4

and cannot mean 0 when R(16) mean OR(17) or SO2CH3;

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5C3F7CH2F, CHF2, OR(17), SO2CH3, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl methylsulfonyl and methylsulfonylamino;

R(17) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3 - or 4-pyridyl,

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

R(3) means CHR(18)R(19),

where R(18) means a hydrogen atom or a CzH2z-R(16),

moreover, R(16) has the above meaning; z is 0, 1, 2 or 3;

R(19) means COOH, CONH2, CONR(20)R(21), COOR(22) or CH2OH,

where R(20) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, CvH2v-CF3or CwH2w-phenyl,

moreover, the phenyl ring is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom or alkyl with 1, 2, 3, 4 or 5 atoms ug is erode;

R(22) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(4) means a hydrogen atom, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;

or

R(3) and R(4) together imply a chain of 4 or 5 methylene groups, of which one methylene group may be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl)-;

R(5), R(6) R(7) independently of one another denote F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31) independently of one another mean a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

or

R(30) R(31) together mean an oxygen atom or a chain of 2 methylene groups;

and their pharmaceutically acceptable salts.

Preferred compounds of formula (Ia) and formula (Ib),

where X means an oxygen atom or a sulfur atom;

R(1) means C(O)OR(9), SO2R(10), COR(11), C(O)NR(12)R(13);

moreover, R(9)R(10)R(11) R(12) independently of one another denote WithxH2-R(14),

where x is 0, 1, 2, 3 or 4, and x cannot mean 0 when R(14) mean OR(15);

R(14) denotes alkyl with 1, 2, 3, 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9 carbon atoms, CF3, OR(15), phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic the STATCOM with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3or phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(13) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(2) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(3) meansyH2y-R(16),

where y is 0, 1, 2, 3,or 4

and cannot mean 0 when R(16) mean OR(17) or SO2CH3;

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9 carbon atoms, CF3, OR(17), SO2 CH3, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3 - or 4-pyridyl,

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino; or

R(3) means CHR(18)R(19),

where R(18) means a hydrogen atom or a CzH2z-R(16),

moreover, R(16) has the above meaning;

z is 0, 1, 2 or 3;

R(19) means CONH2, CONR(20)R(21), COOR(22) or CH2OH,

where R(20) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, Csub> vH2v-CF3or CwH2w-phenyl,

moreover, the phenyl ring is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom or alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(22) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(4) means a hydrogen atom, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;

R(5), R(6) R(7) independently of one another denote F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31) independently of one another mean a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms; or

R(30) R(31) together mean a chain of 2 methylene groups;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula (Ia) and formula (Ib),

where X means an oxygen atom or a sulfur atom; R(1) means C(O)OR(9), SO2R(10), COR(11), or C(O)NR(12)R(13);

moreover, R(9)R(10)R(11) R(12) independently of one another denote WithxH2-R(14),

where x is 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5C3F7CH2F, CHF2, OR(15), phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3or phenyl which is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino the group; and R(13) means a hydrogen atom;

R(2) means a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

R(3) means CHR(18)R(19),

where R(18) means a hydrogen atom or a CzH2z-R(16),

moreover, R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9 carbon atoms, CF3, OR(17), SO2CH3, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3 - or 4-pyridyl,

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and IU is isalphanumeric; z is 0, 1, 2 or 3;

R(19) means CONH2, CONR(20)R(21), COOR(22) or CH2OH,

where R(20) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, CvH2v-CF3or CwH2w-phenyl,

moreover, the phenyl ring is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom or alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(22) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(4) means a hydrogen atom, alkyl with 1 or 2 carbon atoms;

R(5), R(6) R(7) independently of one another denote F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31) independently of one another mean a hydrogen atom or methyl;

and their pharmaceutically acceptable salts. Highly preferred compounds of formula (Ia) and formula (Ib),

where X means an oxygen atom or a sulfur atom;

R(1) OSN which includes C(O)OR(9), SO2R(10), COR(11), or C(O)NR(12)R(13),

moreover, R(9)R(10)R(11) R(12) independently of one another denote WithxH2-R(14),

where x is 0, 1, 2, 3 or 4;

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5C3F7CH2F, CHF2, SO2CH3, phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino; and

R(13) means a hydrogen atom;

R(2) means a hydrogen atom or methyl;

R(3) meansyH2y-R(16),

where y is 0, 1, 2, 3 or 4, and cannot mean 0 when R(16) mean OR(17);

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5C3F7CH2F, CHF2, OR(17), SO2CH3, phenyl, naphthyl, furyl, thienyl or N-containing gets auromatically balance 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic residue is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3 - or 4-pyridyl,

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4) means a hydrogen atom or alkyl with 1 or 2 carbon atoms;

R(5), R(6) R(7) independently of one another denote F, Cl, Br, I, CF3, NO2CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31) independently of other the and denote a hydrogen atom or methyl;

and their pharmaceutically acceptable salts.

In particular, preferred compounds of formula (Ia) or (Ib),

where R(1) means C(O)OR(9), SO2R(10), COR(11), or C(O)NR(12)R(13);

moreover, R(9)R(10)R(11) R(12) independently of one another denote WithxH2-R(14),

where x is 0, 1, 2 or 3;

R(14) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl or pyridyl,

moreover, the phenyl and pyridyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, OH, alkyl with 1, 2, 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms; and

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

R(3) meansyH2y-R(16),

where y denotes 0, 1 or 2; R(16) denotes alkyl with 1, 2 or 3 carbon atoms, cycloalkyl with 5 or 6 carbon atoms, CF3, phenyl or pyridyl,

moreover, the phenyl and pyridyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 carbon atoms or alkoxyl with 1 or 2 carbon atoms;

R(4) means a hydrogen atom;

R(5), R(6) R(7) independently of one another denote F, Cl, CF3CN, COOCH3, CONH2, COCH3, NH2, OH, alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1 or 2 carbon atoms;

R(30) R(31) independently from each other mean a hydrogen atom or methyl;

and their pharmaceutically acceptable salts.

Above all, especially preferred compounds of formula (Ia) and formula (Ib),

where X means an oxygen atom or a sulfur atom;

R(1) means C(O)OR(9) or COR(11),

moreover, R(9) and R(11) independently of one another denote WithxH2-R(14),

where x is 0, 1, 2 or 3;

R(14) means cycloalkyl with 5 or 6 carbon atoms or phenyl,

moreover, the phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, OH, alkyl with 1, 2, 3 carbon atoms or alkoxyl with 1 or 2 carbon atoms;

R(2) means a hydrogen atom;

R(3) meansyH2y-R(16),

where y denotes 0, 1 or 2;

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, cycloalkyl with 5 or 6 carbon atoms, phenyl or pyridyl,

moreover, the phenyl and pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, alkyl with 1, 2 or 3 carbon atoms or alkoxyl with 1 or 2 carbon atoms;

R(4) means a hydrogen atom;

R(5), R(6) R(7) independently of one another denote F, Cl, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1, 2 carbon atoms;

R(30) R(31) denote hydrogen atoms;

and their pharmaceutically acceptable salts.

Proposed according to the invention compounds are still unknown. They are osastot on the so-called Kv1.5 potassium channel and inhibit referred to as "sverhbystro activated slow cleaner" potassium flow in the human atrium. Therefore, compounds highly suitable as a new type of anti-arrhythmic biologically active substances, in particular for the treatment and prevention of atrial arrhythmias, such as atrial fibrillation (atrial fibrillation, AF) or atrial flutter (atrial utter).

Atrial fibrillation (AF) and atrial flutter are often prolonged atrial arrhythmias. Their occurrence increases with increasing age and often leads to fatal consequences, such as bleeding in the brain. AF affects approximately 1 million Americans each year and leads to more than 80,000 cases of haemorrhage each year in the United States. The currently adopted antiarrhythmic agent of class I and class III reduces the rate of reappearance AF, however, because of their potential prioritiesin side effects are only of limited use. Therefore, in medicine there is a great need to create the best medicines for the treatment of atrial arrhythmias (S. Nattel, Am. Heart. J., 130, 1094-1106 (1995): "Newer developments in the management of atrial fibrillation").

It was found that in most cases, supraventricular arrhythmia "subordinate" so-called "circulation" (re-back) wave excitation. Such circulation of excitation" come when cardiac tissue is the possession is t slow conduction and simultaneously short refractory periods. The increase in myocardial refractory time by lengthening of the action potential is a recognized mechanism to terminate arrhythmias, respectively, prevent their occurrence (Colatsky TJ and other Drug Dev. Res., 19, 129-140 (1990): "Potassium channels as targets for antiarrhythmic drug action"). The duration of the action potential is determined essentially by volume repolarizes To+streams that flow through the different+-channels of the cells. Especially great importance attributed to the so-called "slow purifier" IKthat consists of 3 different components: IKrIKsand IKur.

Most of the known antiarrhythmic drugs class III (e.g. dofetilide, E and d-sotalol) predominantly or exclusively block quickly activated potassium channel IKrthat can be detected in cells of the human ventricle (heart), and in the atrium. However, it is shown that these compounds in small or normal frequency of cardiac contractions have increased prioritiesin risk, and in particular see arrhythmia, which is called piruetas fibrillation (D.M. Roden. Am. J. Cardiol., 72, 44B-49B (1993): "Current status of class III antiarrhythmic drug therapy"). Along with this high, partly fatal risk at low frequency, for blockers IKrinstalled the loss of efficiency in the conditions of tachycardia, when you directly impact ("negative correlation with the application).

While some of these disadvantages, it may be possible to eliminate the use of blockers slowly activated component (IKs), their effectiveness is still not proven as unknown no clinical studies blockers IKschannel.

"Especially quickly activated and very slowly inactiveusers slow component purifier IKur(="sverhbystro activated slow purifier"), which corresponds to the Kv1.5 channel, plays a particularly important role in relation to the duration of repolarization in the human atrium. Inhibition of potassium flow outwards IKurthus, compared with the inhibition of IKraccordingly, IKsthat is a particularly effective way of lengthening the atrial action potential and, thus, the termination or prevention of atrial arrhythmias. Mathematical model of human action potential suggests that the positive effect of the blockade of IKurmust be expressed directly in pathological conditions of chronic atrial fibrillation (M. Courtemanche, R.J. Ramirez, and S. Nattel, Cardiovascular Research, 42, 477489 (1999): "Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a matematical model").

In contrast IKrand IKsthat also exist in the human atrium, IKur, however, plays a significant role in the human atrium, but not in the ventricle. Because of this, when the inhibition of IKurstream, in contrast to the blockade of IKror IKsfrom the beginning eliminates the risk proaritmicheskimi effects on ventricular (Z. Wang and others Circ. Res., 73, 1061-1076 (1993): "Sustained Depolarisation-Induced Outward Current in Human Atrial Myocytes"; G.-R. Li and other Circ. Res., 78, 689-696 (1996): "Evidence for Two Components of Delayed Rectifier K+-Current in Human Ventricular Myocytes"; G.J. Amos and others J. Physiol., 491, 31-50 (1966): "Differences between outward currents of human atrialand subepicardial ventricular myocytes").

Antiarrhythmic agent that act by selective blockade of IKurstream, respectively, Kv1.5 channel, still, however, not available for sale. For numerous pharmaceutical biologically active substances (as, for example, tedisamil, bupivacaine or sertindole), however, described blokiruuschaya effect on Kv1.5 channel, however, the blockade of Kv1.5 in this case represents the only side effects along with other key actions of substances.

In international applications WO 98/04521 and WO 99/37607 claimed aminoindane and aminotetrahydrofuran as blockers of potassium channels that block Kv1.5 channel. Also in the international application WO 00/12077 claimed structurally related aminopropane as Kv1.5 blockers. In the international application WO 99/62891 claimed thiazolidinone, which also block the potassium channel. In international applications WO 98/18475 and WO 98/18476 describes the use of different pyridazinones and phosphine oxides as antiarrhythmic drugs, which must act through blockade of IKur. These compounds initially, however, described +96 as immunosuppressants (international application WO 96/25936). All compounds described in the above applications, have the structure of a completely different kind than what is offered in accordance with the present invention the connection. For all stated in the above applications of the compounds of the authors of this proposal is unknown no clinical data.

Now suddenly it is shown that described in this application allrounda amides furan - and thiencarbazone acids are potent blockers of human Kv1.5 channel. Therefore, they can be used as a new type of antiarrhythmic drugs with a particularly preferred security profile. Compounds particularly suitable for the treatment of supraventricular arrhythmias, such as flicker or atrial flutter.

Connections can be used for termination of existing scintillation or the same ones fibrillation, to achieve again sinus rhythm (cardioversion). Over tor is, substance reduces the propensity for the emergence of new phenomena flicker (achieving sinus rhythm, prevention).

Proposed according to the invention compounds are still unknown.

In the case of compounds of formula (I) in the present invention it is thus always on the compounds of formulas (Ia) and formula (Ib).

According to the invention, alkyl and alkylene residues may be linear or branched. This also applies to alkilinity the remnants of the formula CxH2WithyH2CzH2zCvH2vand CwH2w. Alkyl and alkylene residues may be linear or branched, if they substituted or contained in other residues, for example, in the CNS residue or fluorinated alkyl residue. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Needell, eicosyl. Produced from these divalent residue remains, as, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, 1,5-pentile, 2,2-dimethyl-1,3-propylene, 1,6-hexylen, and so on, are the two who are examples alkilinity residues.

Cycloalkyl residues can also be branched. Examples cycloalkyl residues 3-11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, 2-methylcyclohexyl, 3-methylcyclobutene, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, mental, cycloheptyl, cyclooctyl, etc.

As the N-containing heteroaromatic residues with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are set in features 1-, 2 - or 3-pyrrolyl; 1-, 2-, 4 - or 5-imidazolyl; 1-, 3-, 4 - or 5-pyrazolyl; 1,2,3-triazole-1-, -4 - or-5-yl; 1,2,4-triazole-1-, -3 - or-5-yl; 1 or 5 tetrazolyl; 2-, 4 - or 5-oxazolyl; 3-, 4 - or 5-isoxazolyl; 1,2,3-oxadiazol-4 - or-5-yl; 1,2,4-oxadiazol-3 - or-5-yl; 1,3,4-oxadiazol-2-yl or-5-yl; 2-, 4 - or 5-thiazolyl; 3-, 4 - or 5-isothiazolin; 1,3,4-thiadiazole-2 - or-5-yl; 1,2,4-thiadiazole-3- or-5-yl; 1,2,3-thiadiazole-4 - or-5-yl; 2-, 3 - or 4-pyridyl; 2-, 4-, 5 - or 6-pyrimidinyl; 3 - or 4-pyridazinyl; pyrazinyl; 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl; 1-, 2-, 4 - or 5-benzimidazolyl; 1-, 3-, 4-, 5-, 6- or 7-indazole; 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin; 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic; 2-, 4-, 5-, 6-, 7 - or 8-hintline; 3-, 4-, 5-, 6-, 7 - or 8-cinnoline; 2-, 3-, 5-, 6-, 7- or 8-honokalani; 1-, 4-, 5-, 6-, 7 - or 8-phthalazine. Next, cover the corresponding N-oxides of these compounds, therefore, for example, 1-hydroxy-2-, -3 - or 4-pyridyl.

Especially preferred are the I N-containing heterocycles pyrrolyl, imidazolyl, hinely, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Pyridyl means 2-, 3-, and 4-pyridyl. Thienyl means both 2-and 3-thienyl. Furyl means both 2-and 3-furyl.

Monosubstituted phenyl residues can be substituted in 2-, 3 - or 4-position; disubstituted in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions; in tizamidine 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-positions. Appropriate, in the sense that similarly has a value for N-containing heteroaromatic residues, thiophene or fueling balance.

In the case of double or triple substitution, the substituents may be the same or different.

When R(3) and R(4) together imply a chain of 4 or 5 methylene groups, of which one methylene group may be replaced by-O-, -S-, -NH -, and so on, then these residues, together with the nitrogen atom according to formula (I) form a 5 - or 6-membered nitrogen-containing heterocycle, such as, for example, pyrrolidine, piperidine, morpholine, thiomorpholine etc.

If the compounds of formula (I) contain one or more acidic or basic groups, one or more basic compounds, the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically applicable salt. Thus, the compounds of formula (I)comprising acidic groups, for example, one or a few is to COOH groups, you can apply, for example, in the form of salts of alkali metals, preferably sodium or potassium salts, or as salts of alkaline earth metals, e.g. calcium or magnesium salts, or as ammonium salts, such as salts with ammonia or organic amines or amino acids. The compounds of formula (I), which include one or more primary, that is, protonium, groups, or contain one or more basic heterocycles, can be applied in the form of their physiologically acceptable additive salts with inorganic or organic acids, for example, in the form of hydrochloride, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malatov, gluconate, etc. If the compounds of formula (I) contain in the molecule at the same time acidic and basic groups, along with these salt forms of the invention also includes internal salts, the so-called betaines. Salt can be obtained from compounds of formula (I) by conventional means, for example, by combining with the acid or base in a solvent or dispersant, or by anion exchange from other salts.

The compounds of formula (I) with the appropriate substitution may be present in stereoisomeric forms. If the compounds of formula (I) contain one or more asymmetric centers, it is independently of one another have the S - or R-configuration. The invention includes all possible stereoisomers, such as enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, for example, enantiomers and/or diastereomers, in all ratios. Therefore, to the invention include, for example, the enantiomers in the form of pure enantiomers, in the form of left-, and programada antipodes, and also in the form of mixtures of both enantiomeres in different ratios or in the form of racemates. Individual stereoisomers can be obtained in the desired case, by separating the mixture by conventional means, for example, or by stereoselective synthesis. In the presence of mobile hydrogen atoms, the present invention relates to all tautomeric forms of the compounds of formula (I).

The compounds of formula (Ia) and formula (Ib) are obtained by various chemical methods, which also belong to the present invention. Some typical ways of obtaining presents the following schemes 1-4. X and residues R(1)-R(7), R(30) R(31), respectively, have the above values, if, further, do not specify anything else.

For example, the compound of formula (Ib) are obtained according to scheme 1 (method A) or scheme 2 (method B). Similarly it is possible to obtain the compounds of formula (Ia) when the corresponding halides of the formula (IIIa) (structure see figure 4).

Allrounda amides furan - and thiencarbazone acids of the formula (IVb) can be obtained by catalyzed by palladium reaction mix according to Suzuki (which can be done, for example, in the presence of Pd[P(C6H5)3]4as a catalyst, sodium carbonate as a base and 1,2-dimethoxyethane as solvent) aromatic halide of the formula (IIIb) with aromatic Bronevoy acid of formula (II). When R(9) means easy tseplyalsya the rest, as, for example, tert-butyl or benzyl, can be obtained the compounds of formula (Vb), then by entering into interaction with the reagents R(1)-Z and/or R(2)-Y can be converted to compounds of formula (I). Interaction of the compounds of the formula (Vb) with compounds of formula R(1)-Z correspond to the well-known conversion of amine to amide carboxylic acid amide sulfonic acids, a carbamate derivative of urea or thiourea. The residue Z this means suitable nucleofuge delete the group, such as F, Cl, Br, imidazolyl, operations group.

To obtain the compounds of formula (Ib)in which R(1) means C(O)OR(9), therefore, carbamates, for example, use of the compounds of formula R(1)-Z, in which Z denotes a chlorine atom or O-operations group, therefore, chloroformate or succinimidylester.

To obtain the compounds of formula (Ib)in which R(1) who appoints SO 2R(10)therefore, sulfonamides, using, as a rule, the compounds of formula R(1)-Z, in which Z denotes a chlorine atom, therefore, the anhydrides of sulfonic acids.

To obtain the compounds of formula (Ib)in which R(1) means COR(11), therefore, amides of carboxylic acids, are used, for example, the compounds of formula R(1)-Z, in which Z denotes a chlorine atom, an imidazole or acetochlor, therefore, carboxylic acid anhydrides, imidazolides carboxylic acids or mixed anhydrides. However, you can also use the free acid of the formula R(1)-OH in the presence of a suitable condensing means, as carbodiimide or TFFH.

To obtain the compounds of formula (Ib)in which R(1) means CONR(12)R(13) or C(S)NR(12)R(13)therefore, ureas or thioureas, instead of the compounds of the formula R(1)-Z is also possible to use compounds of the formula R(12)N(=C=O), respectively, R(12)N(=C=S), therefore, isocyanates or thioisocyanate.

Allrounda amides furan - and thiencarbazone acids of the formula (VIIIb) can be obtained by catalyzed by palladium reaction combinations for Suzuki aromatic bromide or iodide of the formula (VIIb) with aromatic Bronevoy acid of formula (II). Hydrolysis of ester using LiOH leads to the free acids of the formula (IXb), which by reaction combination with other amines(3)R(4) p is levaditi in bizarely formula (IVb). As shown in scheme 1, the separation of labile group R(9) leads to compounds of the formula (Vb), which then can be converted into compounds of formula (Ib). Similarly it is possible to obtain the compounds of formula (Ia) by applying the corresponding halides of the formula (VIIa) (structure see figure 4).

The above interaction of compounds of formula (IXb) with amines of the formula HNR(3)R(4) correspond to the well-known transformation of the carboxylic acid in the carboxylic acid amide. For these reactions the literature describes numerous ways. Especially preferably, they can be done by activating carboxylic acids, for example, using dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-(3-dimethylaminopropyl)carbodiimides (EDC), if necessary, with the addition of hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP). But first, can be synthesized by known methods reactive derivatives of acids, for example anhydrides of the acids, by introducing into the interaction of carboxylic acids of the formula (IX) or with inorganic halogenide acids, such as SOCl2or imidazolidine acids by reacting with the carbonyl diimidazol, which are then, if necessary, with the addition of an auxiliary base, enter into interaction with amines of the formula HNR(3)R(4).

p>

Necessary ways and aromatic boranova acid of formula (II) can be synthesized from aromatic compounds or aromatic halides of the formula (VI) by the introduction of lithium in the o-position or due to the exchange of halogen to metal with subsequent introduction into interaction with trimethylamin ester of boric acid (or other complex trifiro boric acid) and subsequent acidic hydrolysis.

Used in the way In the halides of the formulas (VIIa) and (VIIb) are synthesized according to known literature methods, they are easy to get conventional methods of esterification known from the literature acids of the formula (X). Used in the method And aromatic ortho-halogenated formula (IIIa) and formula (IIIb) are obtained according to scheme 4 from esters of formula (VIIa) and formula (VIIb) after hydrolysis to the acid of formula (XA) and (Xb) by reaction combination with other amines(3)R(4). The formation of amide linkages can be achieved by the methods described above for the conversion of compounds of formula (IXb) in the compounds of formula (IVb).

In the case of all methods may be necessary at certain stages of the reaction temporarily protected functional group. Such methods of introducing protective groups known to the specialist. The choice of protective groups used for functional GRU is p and the ways of their introduction and removal are described in the literature and, if necessary, can easily be adapted to the specific occasion.

Proposed according to the invention compounds of formula (Ia) and (Ib) and their physiologically acceptable salts can be applied in the case of an animal, preferably a mammal, and especially a human, in the quality of medicines individually, as mixtures with one another or in the form of pharmaceutical compositions. The object of the present invention are also compounds of formulas (Ia) and (Ib) and their physiologically acceptable salts are suitable as pharmaceuticals, their use for the treatment and prevention of these paintings diseases and their application to obtain drugs for these purposes and medicines with blocking To+-channels effect. Further, an object of the present invention are pharmaceutical compositions which contain as an active ingredient an effective dose of at least one compound of formula (Ia) and formula (Ib) and/or its physiologically acceptable salt along with conventional, pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions usually contain 0.1 to 90 wt.% compounds of formula (Ia) and formula (Ib) and/or their physiologically acceptable salts. The pharmaceutical compositions can be obtained in itself known. the La of the compounds of formula (Ia) and formula (Ib) and/or their physiologically acceptable salts together with one or more solid or liquid galenovye carriers and/or excipients and, if it is desired, in combination with other biologically active drugs brought to a suitable form of application or dosage form which can then be used as a drug in human medicine or animal.

Medicines that contain proposed according to the invention the compounds of formula (Ia) and formula (Ib) and/or their physiologically acceptable salts can be administered orally, parenterally, for example intravenously, rectally, by inhalation, or locally, preferably an introduction to a particular case depends, for example, from the corresponding picture of the symptoms of treatable diseases.

What excipients suitable for the desired finished dosage forms, the specialist is known on the basis of his expert knowledge. Besides solvents, gel-forming means, auxiliary materials for the production of tablets and other carriers of biologically active substances can be applied, for example, antioxidants, dispersants, emulsifiers, antispyware, improves the taste of the ingredients, preservatives, promote dissolving agents, agents for achieving a depot effect, buferiruemoi substances or dyes.

The compounds of formula (Ia) and formula (Ib) to achieve the preferable therapeutic action is via can also be combined with other medicinal biologically active substances. So, in the case of treatment of cardiovascular diseases, the possible preferred combination with active against cardiovascular substances. As this type is preferred for cardiovascular disease components of the combination use, for example, other antiarrhythmic agent, thus, antiarrhythmic agent of class I, class II or class III, as, for example, blockers IKsor IKrchannel, for example, dofetilide, or, further, blood pressure-lowering substances, such as ACE inhibitors (e.g. enalapril, captopril, ramipril), antagonists of angiotensin, activators To+channel, as well as blockers αand βreceptors, however, also sympathomimetic and adrenergichesky active compounds as inhibitors of Na+/H+exchange, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotrope active substances as, for example, digitalis glycosides or diuretics.

For oral forms of application of active compound is mixed with suitable for this purpose additives, as carriers, stabilizers or inert diluents, and the usual way is transferred to a suitable pharmaceutical form such as tablets, pills, detachable capsules, aqueous, alcoholic or oily solutions. As inert carriers can be used which, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This composition can be obtained as dry and as wet granules. As oily carriers or solvents are used, for example, vegetable or animal oils as sunflower oil or cod-liver oil. As solvents for aqueous or alcohol solutions are used, for example, water, ethanol or solutions of sugars or mixtures thereof. Other auxiliary substances, also for other forms of application are, for example, glycols and polypropylenglycol.

For subcutaneous or intravenous administration, the active compounds, desirable in the case of using the conventional for this purpose substances as contributing to the dissolved substances, emulsifiers or other auxiliaries, transferred into a solution, suspension or emulsion. The compounds of formula (Ia) and formula (Ib) and their physiologically acceptable salts can also be liofilizirovanny and received lyophilizate be used, for example, for the preparation of drugs for injection or infusion. As the solvent used, for example, water, physiological sodium chloride solution or alcohols, e.g. ethanol, propanol, glycerin, along with them also solutions of sugars, as solutions Chapter the goats or mannitol, or also mixtures of these various specified solvents. As pharmaceutical compositions for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of biologically active substances of the formula (Ia) and formula (Ib) or their physiologically acceptable salts in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or mixtures of such solvents. If necessary, the composition may also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as the propellant. This composition contains biologically active substance is usually in a concentration of from about 0.1 wt.% up to 10 wt.%, in particular from about 0.3 wt.% up to 3 wt.%.

Dosage introduce biologically active substances of the formula (Ia) and formula (Ib), respectively, of its physiologically acceptable salts, depends on the specific case and must be adapted, as usual, for the optimal action in a particular case. So, it depends, of course, on the frequency of administration and strength, and duration used, respectively, for the treatment or prevention of compounds, but also on the nature and intensity of treatable diseases, as well as gender, age, weight and individual sensitivity Isle Ivanovo person or animal, and do the treatment prophylactically or in the period of exacerbation. Usually, the daily dose of the compounds of formula (Ia) and formula (Ib) in the case of the introduction of patient weighing approximately 75 kg is from about 0.001 mg/kg body weight to 100 mg/kg body weight, preferably from 0.01 mg/kg body weight to 20 mg/kg of body weight. Dose can be administered as a single dose or divided into several, for example two, three or four doses. In particular in the treatment of cases of exacerbation of cardiac arrhythmias, for example, in the ICU, it may be also preferable to parenteral administration by injection or infusion, for example, by continuous intravenous infusion.

Experimental part

List of abbreviations:

Vostert-Butyloxycarbonyl
CDICarbonyldiimidazole
DCCDicyclohexylcarbodiimide
DMAP4-dimethylaminopyridine
DMFN,N-dimethylformamide
DME1,2-dimethoxyethan
EDCN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide
HOBt1-hydroxy-1H-benzotriazol
IUMethyl
MeLi Motility (in hexane)
BuLiUtility (pentane)
RP-HPLCHPLC with reversed-phase
THFTetrahydrofuran
TFFHTetramethylpropylenediamine
ES+Ionization electron spray with the formation of positive ions
FABThe fast atom bombardment

Synthesis Baranovich acids of the formula (II)

Boranova acid synthesized according to scheme 3 synthesis is demonstrated on the example of several compounds:

2-(tert-Butoxycarbonylamino)phenylboronic acid (compound 1)

N-Boc-2-bromobenzylamine in the number 5,72 g (20 mmol) in argon atmosphere was dissolved in tetrahydrofuran, cooled to a temperature of -78aboutWith mixed with some of 13.75 ml of a 1.6 M solution metallice in hexane (22 mmol)after 1 hour, mixed with 28 ml of a 1.5 M solution of tert-utility in pentane (42 mmol) and after aging in the next hour at a temperature of -78aboutTo add 9.0 ml (80 mmol) trimethylol ester of boric acid. After heating to room temperature, mixed with diluted hydrochloric acid to pH 6, and extracted with dichloromethane, the organic phase is washed with saturated RA is tworoom of sodium chloride and dried. Get a 5.1 g (100%) solid foam light yellow color.

Mass spectrum (FAB; the sample is mixed with glycerol): m/z=308 (M+57); 252 (M+1).

(R)-2-(1-tert-Butoxycarbonylamino)phenylboronic acid (compound 2)

2.2 g (10 mmol) N-Boc-(R)-phenethylamine dissolved in 50 ml of anhydrous tetrahydrofuran, cooled to a temperature of -78aboutWith dropwise and mixed with 14 ml of a 1.5 M solution of tert-utility in pentane (21 mmol). For 2 hours, heated to a temperature of -20aboutWith, then add 4.5 ml (40 mmol) trimethylol ester of boric acid and heated to room temperature. The solution is cooled to a temperature of 0aboutC, acidified with 10%HCl to pH 6, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with saturated sodium chloride solution, dried and concentrated. Obtain 2.0 g (75%) solid foam light yellow color, which is used without further purification.

Mass spectrum (FAB; the sample is mixed with glycerol): m/z=322 (M+57); 266 (M+1).

Synthesis of aromatic halides of the formula (IIIa), (IIIb)

General methods of synthesis of compounds of formula (VIIa), (VIIb) with thionyl chloride:

2.5 mmol of the acid of formula (X) with 3 ml of thionyl chloride is refluxed for 4 hours and then concentrated. The crude reaction product is evaporated twice together with Tolu is scrap, treated with 12.5 ml of dichloromethane and mixed with 3 mmol amine other(3)R(4) and 5.5 mmol of triethylamine. The mixture is stirred overnight, washed with a solution of NaHCO3, dried and concentrated. Receive 1.5-2.5 mmol target amide of formula (III), which can be used without further purification.

Amides of formula (IIIa), (IIIb)obtained according to the General method of synthesis:

ConnectionStructureMass spectrum (ES+): m/z=
3308 (M+1)
4364 (M+1)
5260 (M+1)
6316 (M+1)
7316 (M+1)
8260 (M+1)
9380 (M+1)
10324 (M+1)
11276 (M+1)
12 380 (M+1)
13324 (M+1)

Synthesis ALLROUNDER amides furan - and thiencarbazone acids catalyzed by palladium reaction combinations for Suzuki with the formation of compounds of the formulas (IVa) and (IVb)

General synthesis technique

It was saturated with argon 1,2-dimethoxyethane (10 ml/mmol of bromide of formula (IIIa), formula (IIIb)) add 0.05 to EQ. tetranitroaniline and 1 EQ. the corresponding bromide of formula (IIIa), formula (IIIb). After 10 minutes add 1.5 EQ. the corresponding Bronevoy acid of formula (II) and, finally, 2 EQ. 2 M sodium carbonate solution. Refluxed in an argon atmosphere for 18 hours, cooled and diluted with dichloromethane. The mixture is washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated and purified by chromatography. When cleaning using RP-HPLC the main compounds isolated in the form of trifurcation.

Example areleaving amide thiencarbazone acid of the formula (IVa)

Example 1

tert-Butyl ether {2-[2-(3-methylbutanoyl)thiophene-3-yl]benzyl}carbamino acid

10 ml of 1,2-Dimethoxyethane saturated with argon, added 58 mg (0.05 mmol) of Pd[P(C6H5)3]4and 276 mg (1 mmol) 3-methylbutylamine-bromothiophene-2-carboxylic acid. After 10 minutes, add 377 mg (1.5 mmol) of 2-(tert-butoxycarbonylamino)phenylboronic acid and, finally, 1 ml of 2 M sodium carbonate solution. The mixture is refluxed in an argon atmosphere for 18 hours, after cooling, diluted with dichloromethane and washed with water. The organic phase (viscous oil black color), dried, concentrated and chromatographically purified by RP-HPLC. Obtain 51 mg (13%) of a viscous colorless oil. Mass spectrum (ES+): m/z=403 (M+1); 303 (M-99).1H-NMR (CDCl3): δ=7,55-7,21 (5H, m), 6.90 to (1H, d, J=4,8 Hz), to 5.58 (1H, ush. C)4,82 (1H, ush. C)4,10 (2H, d, J=6.2 Hz), 3,18 (2H, m), 1,40 (N, C)of 1.16 (1H, m)of 1.07 (2H, q, J=7.0 Hz), 0.75 in (6N, d, J=6.2 Hz).

Further examples ALLROUNDER amides furan - and thiencarbazone acids of the formula (IVa) and (IVb) (method A):

Accordingly, the above General method of synthesizing compounds according to the following examples:

6
ConnectionStructureMass spectrum (ES+): m/z=
2459 (M+1)
3443 (M+1)
4387 (M+1)
5459 (M+1)
403 (M+1)
7443 (M+1)
8387 (M+1)
9442 (M+1)
10386 (M+1)

The removal of protective BOC-group with the formation of amines (scheme 1 and 2)

General synthesis technique

1 EQ. N-Boc-compound is dissolved in dichloromethane/triperoxonane acid (3/1; 10 ml/mmol) and stirred at room temperature for 3 hours. Then concentrated in a rotary evaporator and evaporated together with the toluene. Amines of formula (V) without further purification used for further transformations. All connections kharakterizovyvatsya using mass spectrometry.

Interaction of amines of the formula (V) with various reagents to form the target compounds of formula (I)

A General method of conversion of the carbamates of the formula (I)

1 EQ. amine of formula (V) is dissolved in dichloromethane (about 10 ml/mmol), mixed with 1.2 EQ. (2.2 EQ. when using trifenatate) of triethylamine and 1.2 EQ. succinimidylester (or, at the choice of the appropriate chloroformate) and stirred for but is I. Diluted with dichloromethane and washed with sodium hydrogen carbonate solution. The organic phase is dried, concentrated and, if necessary, purified using RP-HPLC.

Example 11

Benzyl ether {2-[2-(3-methylbutanoyl)thiophene-3-yl]benzyl}carbamino acid

27 mg (0.09 mmol) (3-methylbutyl)amide 3-(2-aminomethylphenol)thiophene-2-carboxylic acid is dissolved in 3 ml of anhydrous dichloromethane, mixed with 10 mg (0.1 mmol) of triethylamine and 24 mg (0.1 mmol) of benzyloxycarbonylglycine. After 18 hours, diluted with 20 ml dichloromethane, washed with saturated sodium hydrogen carbonate solution and the organic phase is dried and concentrated. After purification using RP-HPLC obtain 27 mg (70%) of a colorless substance. Mass spectrum (ES+): m/z=437 (M+1).1H-NMR (CDCl3): δ=7,54-7,24 (10H, m), 6.90 to (1H, d, J=4,8 Hz), 5,52 (1H, ush. C)of 5.05 (3H, ush. C)to 4.17 (2H, d, J=6.2 Hz), and 3.16 (2H, m)to 1.14 (1H, m)of 1.07 (2H, q, J=7.0 Hz), 0, 73 (6N, d, J=6.2 Hz).

Further examples of compounds obtained respectively (above) technique:

ConnectionStructureMass spectrum (ES+): m/z=
12493 (M+1)
13421 (M+1)
14 477 (M+1)
15437 (M+1)
16493 (M+1)
17421 (M+1)
18477 (M+1)
19477 (M+1)

A General method of conversion into amides of formula (I)

A) 1 EQ. amine of formula (V) is dissolved in dichloromethane (about 10 ml/mmol), mixed with 1.2 EQ. (2.2 EQ. when using trifenatate) diisopropylethylamine and 1.2 EQ. the carboxylic acid and stirred over night. Diluted with dichloromethane and washed with sodium hydrogen carbonate solution. The organic phase is dried, concentrated and, if necessary, purified using RP-HPLC.

In) 1 EQ. amine of formula (V) is dissolved in dichloromethane (about 10 ml/mmol), mixed with 1.2 EQ. (2.2 EQ. when using trifenatate) diisopropylethylamine, 1,2 EQ. acid and 1,2 EQ. TFFH and stirred over night. Diluted with dichloromethane and washed with sodium hydrogen carbonate solution. The organic phase is dried, concentrated and, if necessary, purified using RP-HPLC.

Examples of the compounds obtained according to the General methods of work And or:

ConnectionStructureMass spectrum (ES+): m/z=
20435 (M+1)
21491 (M+1)
22451 (M+1)
23507 (M+1)
24451 (M+1)
25507 (M+1)
26435 (M+1)

27491 (M+1)
28435 (M+1)
29491 (M+1)

Pharmacological studies

Kv1.5 channels of a person expressed in Xenopus oocytes. First, oocytes were isolated from Xenopus laevis and depolymerase. Then in these oocytes were injected with in vitro synthesized, encoding Kv1.5 RNA. After the expression of Kv1.5 protein in ECENA 1-7 days was measured Kv1.5-flows in the oocyte by the method of fixed bias voltage using two microelectrodes. Kv1.5 channels at the same time, usually activated with lasting 500 MS voltage steps to 0 mV and 40 mV. The bath was washed with a solution of the following composition: 96 mmol NaCl; 2 mm KCl; 1.8 mmol CaCl2; 1 mmol MgCl2; 5 mmol HEPES (titrated with NaOH to pH 7.4). These experiments were carried out at room temperature. For data collection and analysis used Geneclamp amplifier (Axon Instruments, Foster City, USA) and the Converter MacLab D/A and software (ADInstruments, Castle Hill, Australia). Proposed according to the invention substances tested, the fact that they were added to the electrolyte at different concentrations. Effects of substances was calculated as the inhibition percentage of the control flow Kv1.5, which was obtained when the solution did not add any substance. Data are then extrapolated using the hill equation to determine the inhibitory concentrations of IR50(inhibiting 50% concentration for the substance.

Thus, for the following compounds defined by the following values IR50:

1
ExampleIR50< / br>
[µmol]
ExampleIR50< / br>
[µmol]
ExampleIR50< / br>
[µmol]
ExampleIR50< / br>
[µmol]
42539410
53,16<10071085,2
9<10010<100113122
135,614<100151,2161,9
172,2185,219<10020<100
21a 3.9221,7231,2242,2
251,526a 3.9276,628<100
294,2

1. Allrounda amides furan - or thiophenecarboxylic acids of formulas Ia and Ib:

where

X about the mean oxygen atom or a sulfur atom;

R(1) means C(O)OR(9) or COR(11);

moreover, R(9) and R(11)

independently of one another denote CxH2x-R(14), where

x represents 0, 1, 2 or 3,

moreover, R(14) means phenyl,

moreover, the phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of alkoxyl with 1 or 2 carbon atoms;

R(2) means a hydrogen atom;

R(3) means CyH2y-R(16), where

y means 0, 1 or 2,

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, phenyl, and phenyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I;

R(4) means a hydrogen atom;

R(5), R(6) R(7) denote a hydrogen atom;

R(30) R(31) denote a hydrogen atom;

and their pharmaceutically acceptable salts.

2. The compounds of formula (Ia) and formula (Ib) according to claim 1, where

X means an oxygen atom or a sulfur atom;

R(1) means C(O)OR(9) or COR(11);

moreover, R(9) and R(11)

independently of one another denote CxH2x-R(14), where

x represents 0, 1, 2 or 3,

moreover, R(14) means phenyl,

moreover, the phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of alkoxyl with 1 or 2 carbon atoms;

R(2) means a hydrogen atom;

R(3) means CyH2y-R(16), where

y means 0, 1 or 2,

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, phenyl, and phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl;

R(4) means a hydrogen atom;

R(5), R(6) R(7) denote a hydrogen atom;

R(30) R(31) denote a hydrogen atom;

and their pharmaceutically acceptable salts.

3. The compounds of formula (Ia) and formula (Ib) according to claim 1 or 2,

where

X means an oxygen atom or a sulfur atom;

R(1) means C(O)OR(9) or COR(11);

moreover, R(9) and R(11)

independently from each other mean WithxH2-R(14), where

x represents 0, 1, 2 or 3,

moreover, R(14) means phenyl,

moreover, the phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of alkoxyl with 1 or 2 carbon atoms;

R(2) means a hydrogen atom;

R(3) means CyH2y-R(16), where

y means 0, 1 or 2,

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, phenyl, and phenyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl;

R(4) means a hydrogen atom;

R(5), R(6) R(7) denote a hydrogen atom;

R(30) R(31) denote a hydrogen atom;

and their pharmaceutically acceptable salts.

4. The compounds of formula (Ia) and formula (Ib), one of the Il is more of claims 1 to 3, and their pharmaceutically acceptable salts, possess antiarrhythmic activity.

5. Pharmaceutical composition having anti-arrhythmic activity, containing an effective amount of at least one compound of formula (Ia) or (Ib) according to one or more of claims 1 to 4 and/or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carriers and additives.

6. The use of the compounds of formula (Ia) and formula (Ib) according to one or more of claims 1 to 4 and/or its pharmaceutically acceptable salt to obtain medicines with blocking To+-channel effect for the treatment or prevention of mediated+channel diseases.

7. The use according to claim 6 for the treatment or prevention of cardiac arrhythmias, which can be eliminated by lengthening of the action potential.

8. The use according to claim 6 for the treatment or prevention of arrhythmias due to recurrent excitation.

9. The use according to claim 6 for the treatment or prophylaxis of supraventricular arrhythmias.

10. The use according to claim 6 for the treatment or prophylaxis of atrial fibrillation or atrial utter.

11. The use according to claim 6 for terminating atrial fibrillation or atrial utter (cardioversion).



 

Same patents:

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

The invention relates to new derivatives of amidine General formula (I’)

where it is:

in which R1, R2and R3HE or1-C6alkyl, C1-C6alkoxy, R4- H1-C6alkyl, R5- H1-C6alkyl or the radical:

where R10, R11and R12- OH or H, R13- H1-C6alkyl; or the radical:

where R18, R19and R20- H, HE, C1-C6alkyl, R21and R22- H, C1-C6alkyl, or R21-alkylsulfonyl, alkylsulfonyl, alkylaryl, and R22- H or the radical:

where T is -(CH2)k-, k = 1, 2, R27- H, C1-C6alkyl

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to inhibitors of potassium channel, in particular a derivative of tetrahydronaphthalene formula (I) or their pharmaceutically acceptable salts, stereoisomers, crystalline or amorphous forms

< / BR>
where t is 1; a and b each represent H; R1represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; provided that when R1represents optionally substituted aryl, R1is not dialkoxybenzene; Y2represents (CH2)qwhere q is 0; X2is SO2; R3represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of atom N; R2represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; Y1represents (CH2)pwhere p is 1; NS=SN or ethinyl; X1is C=O or (CH2)nwhere n is 0, 1 or 2; R4represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of carbon atoms and contains nitrogen as heteroatom

The invention relates to the field of medicine and relates to a method of increasing the expression of molecular chaperone cell and/or increasing the activity of molecular chaperones in cells by treating the cells an effective amount of hydroxylamine derivative of the formula (I) or (II), as well as to new derivatives of hydroxylamine and farmkompanijam based on them

The invention relates to new compounds for combating pests, in particular derivatives carbanilide and fungicide-insecticidal tool based on them

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to new chemical compounds, namely, esters of 2-furfurylamine-2-tsianuksusnogo acid of General formula

< / BR>
where R: CH2CF3(Ia), CH(CF3)2(IB), CH2(CF2)2CF3(IB), CH2(CF2)4H (Iك), CH2PhX (Ia), CH2C(CH3)(X)2(S), CH2C2H5)(X)2(AI), CH2WITH(X)3(IK),

when X

< / BR>
These compounds can be used as an inhibitor to prevent premature polymerization of unsaturated compounds in their synthesis, processing and storage, such as methyl methacrylate, styrene, dimethylphenylcarbinol, ethyl-2-cyanoacrylate and other

The invention relates to dimethylpolysiloxene General formula

< / BR>
in which the radicals R1and R2may be the same or different, represents hydrogen, C2-C6- alkyl, C3-C6-cycloalkyl, C3-C6alkenyl,

C2-C6-quinil, C1-C3-halogenated, benzoyloxy group containing substituents, benzoylamino, which can also contain one or two Deputy, C2-C6-alkanolamines, C3-C6-cycloalkylcarbonyl, benzyl group which may contain substituents, the phenyl group with possible alternates, and other substituents, provided that at the same time R1and R2are not hydrogen atoms, the second condition is that one of R1and R2is not unsubstituted phenyl group when the other one represents a hydrogen atom, and the third condition is one of R1and R2in anthopology is not an aniline ring, C2-C6-alkyl, C3-C6-cycloalkyl or C2-C6-alkoxygroup when the other one represents a hydrogen atom

The invention relates to new methods of obtaining salt orthocarbonate acids or alcoholate hem-triolo having the structural formula R-Me where R is phenyl, furyl, R1-CH= CH-, CH3-(CH= CH)2- CH= C-CH3; Me - Na, K; Rlis phenyl, furyl, used as an intermediate reagents in organic synthesis, as well as in the printing industry for the regeneration of aluminum plates

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethacyzine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 5 ex, 2 tbl

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